The construction of the nervous system is an integrated series of developmental steps, commencing with the segregation of a small group of embryonic cells fated to become neural progenitors. These neural progenitors then remain proliferative and undifferentiated until they have become committed to distinct neural cell fate. As in most neural tissue, within the vertebrate retina, the cell and molecular strategies that cells use to control these processes remain poorly understood. Even worse, most forms of cancer exhibit distinctly misregulated control over these events, and the nature underlying many human diseases are tied to perturbations in these processes. Therefore, the overarching goal of this proposal is to enhance our understanding of the intracellular mechanisms governing neuroblast proliferation, lineage commitment and differentiation within the developing vertebrate retina. This will be accomplished by utilizing the zebrafish retina to understand the role of the intrinsic factor Id2 (Inhiibitor of Differentiation) in retinal development. The specific Aims of this proposal are 1. To determine the function of Id2 during zebrafish retinogenesis, 2. To determine the molecular mechanisms underlying Id2 function in the developing zebrafish retina, and 3. To determine if Id2 is regulated by the Sonic Hedgehog Pathway (Shh). These Aims will be accomplished using Id2 loss and gain-of-function strategies in vivo in order to define the functional role of Id2 during zebrafish retinogenesis, and Shh loss and gain-of-function methods will also be used to assess if Id2 is regulated by Shh in the developing vertebrate retina. The experiments in this proposal will shed light on how the intrinsic factor Id2 regulates growth and differentiation of the vertebrate eye, and how it's function may be controlled by mitogenic properties of the Shh signaling pathway. As the formation of many human neurological, developmental and cancerous diseases are linked to disruptions in such early developmental processes as cell division, cell specialization and cell survival, the purpose of this study is to enhance our understanding of how these processes normally occur at the molecular level within the cell, and how they are controlled over developmental time. Specifically, this study will examine how these events occur in the developing retina, thereby increasing our knowledge of how the retina forms, and providing clues to the events that may be disrupted in the early stages of cancer, such as retinoblastoma, as well as neurodegenerative diseases affecting the retina. [unreadable] [unreadable] [unreadable]